Acute antibody-mediated rejection (AMR) occurs in a small minority of sensitized liver transplant recipients. Although histopathologic characteristics have been described, specific features that could be used: a) for a generalizable scoring system; and b) to trigger a more in-depth analysis are needed to screen for this rare but important finding. Toward this goal, we created a training and validation cohort from 3 high volume liver transplant programs of putative acute AMR and control cases that were evaluated blindly by 4 independent transplant pathologists. Evaluations were performed on H&E sections alone without knowledge of either serum DSA results or C4d stains. Routine histopathological features strongly correlated with severe acute AMR included portal eosinophilia, portal vein endothelial cell hypertrophy, eosinophilic central venulitis, central venulitis severity, and cholestasis. Acute AMR inversely correlated with lymphocytic venulitis and lymphocytic portal inflammation. These and other characteristics were incorporated into models created from the training cohort alone. The final Acute-AMR (aAMR) score (portal vein endothelial cell hypertrophy + portal eosinophilia + eosinophilic venulitis / lymphocytic portal inflammation + lymphocytic venulitis) exhibited a strong correlation with severe acute AMR in the training (OR=2.86, p<0.001) and validation cohort (OR=2.49, p<0.001). SPSS tree classification was used to select 2 cutoffs, one that optimized specificity at a score >1.75 (sensitivity = 34%, specificity = 87%) and a second that optimized sensitivity at a score >1.0 (sensitivity = 81%, specificity = 71%). In conclusion, routine histopathological features of aAMR score can be used to screen for acute AMR on routine H&E in indication liver transplant biopsies, however, a definitive diagnosis requires substantiation by donor-specific HLA alloantibody testing, diffuse C4d staining, and exclusion of other insults. Liver Transpl , 2014. © 2014 AASLD.